Method of production of 5-o-methoxyphenoxymethyl-2-oxazolidone



2,895,960 Patented July 21, 1959 [ice METHOD OF PRODUCTION OFS-o-METHOXY- PHENOXYMETHYL-Z-OXAZOLIDONE Carl D. Lunsford, Richmond,Va., assignor to A. H. Robins Company, Inc., Richmond, Va., acorporation of Virginia No Drawing. Application June 26, 1958 Serial No.744,660

7 Claims. (Cl. 260-307) The present invention concerns itself with anovel process for the production of -aryloxymetl1yl-2oxazolidones whichare extra cyclic ether linked heterocyclic oxazolidone compounds. Moreparticularly the present invention relates to an improved process forthe production of 5-o-methoxyphenoxy-Z-oxazolidone.

This application is a continuation-in-pare of my copending applicationSerial No. 680,647, Lunsford, filed August 28, 1957. In that applicationis disclosed a process of producing5-o-rnethoxyphenoxymethyl-Z-oxazolidone by the fusion of about 2 molequivalents of urea with about 1 mol equivalent of the guaiacol ether ofglycerol or the guaiacol ether of glycerol chlorhydrin. The fusion ofthe reactants to form the oxazolidone ring was achieved by heating inthe range 170 C.200 C. for a period of three to five hours andextracting by means of a suitable solvent. Yields of 23% to 37% of thepure Z-oxazolidone were achieved within this temperature range. Thisreaction in itself was surprising because the normal reaction of ureawith primary alcoholic hydroxyl groups leads to the formation ofcarbamates Organic Synthesis, collective volume one, 140, Davis and Lane(1941), and Kraft, 70, J.A.C.S. 3570 (1948).

It has now been found that by a related process improved yields of purerproducts may be achieved at considerable commercial savings. The presentinvention relates to the fusion of about 1 molar equivalent of urea with1 molar equivalent of 3-o-methoxyphenoxy-2-hydroxy-l-propyl carbamateaccording to the following equation:

The reactants are commercially available.3-o-methoXyphenoxy-Z-hydroxy-l-propyl carbamate (methocarbamol, Robaxin,A. H. Robins Company, Inc., Richmond, Va.), is the subject of US.2,770,649, Murphey. This compound may be conveniently prepared byreacting 3- o-methoxyphenoxy-1,2-propanediol withphosgene to produce theintermediate chlorocarbonate compound and then reacting saidchlorocarbonate with ammonium hydroxide to yield the desired carbamate.

It has further been discovered that the temperature for heating thereactants has a critical lower limit of about 180 C. and preferably inthe range 185 C.-200 C. This raising of the lower limit of thetemperature range from previous practice has been found to bettersuppress undesirable by-products and increase yields both for thepresent reaction and for the prior fusion reaction of about 2 mols ofurea and about 1 mol of glyceryl guaiacol ether previously disclosed inmy parent application Serial No. 680,647, Lunsford, filed August 28,

In the said parent application, yields of 23%-- 37% were achieved whileutilizing the broader tempera ture range of 170 C.-200 CI in the relatedurea process. In the improved process of the present application,utilizing a heating temperature in the upper range of 185 C.200 C.yields of 40%-58% have been'achieved for the pure compound.

It has further been discovered that undesirable byproducts can bereduced by a very rapid heating to the reaction temperature to bringabout the temperature of about 180 C. in the order of one minute orthereabouts.

The reactants are heated together in approximately equimolar proportionsand it is critical for improved yields that two conditions be observed.Firstly, the reactants are rapidly brought to reaction temperature. Inthe laboratory this may be achieved by surrounding the reaction vesselWith a preheated metal bath such as Woods metal and in commercialproduction by equivalent procedures. Secondly, the reactants must beheated to a temperature of about 180 C. and preferably within the rangeC. 200 C. The reactants are heated for a period of about three to fivehours and preferably for five hours to assure complete fusion to producethe desired crude oxazolidone.

Thereafter the crude oxazolidone may be conveniently purified in eitherof two general related methods. One preferred method achieving yields inthe order of 55%- 60% of pure material melting at 141 C.143 C.comprises'extracting the crude product with a solvent such as chloroformor ethyl acetate and fractionally distilling to recover the pureoxazolidone product. A second preferred method achieving yields of 40%and higher comprises recrystallization from an oxygenated solvent, e.g.,alcohols such as ethyl alcohol and ketones such as acetone and water.

The compound which is produced by this invention is related in itspharmacological activity to compounds of well-known therapeutic valuewhich might be characterized as substituted propanediols or glycerylethers, for example, 3-o-toloxy-1,2-propanediol (mephenesin), 3-0-methoxyphenoxy-1,2-propanediol (glycerol guaiacolate),3-o-toloxy-2-hydroxypropyl carbamate (Tolseram, US. 2,609,386, Lott etal.), 2-methyl-2-propyl 1,3-propanediol dicarbamate (mep'robamate,Equanil, US. 2,724,720, Berger et al) and3-'0-methoxyphenoxy-2-hydroxypropyl carbamate (Robaxin, US. 2,770,649,Murphey).

In general the prior art compounds have been found useful for musclerelaxant'conditions susceptible to myanesin therapy where the action iscentral with some slight myoneural depression. The site of thedepression appears to be in the brain stem at the level of the thalamusand in the spinal cord. Such action is characterized by producingWeakness and flaccidity of the skeletal'muscle. The complementarysedative effects of these compounds as well as the muscle relaxantaction are temporary in nature, lasting for mephenesin for a period ofabout an hour after administration.

In contrast to curare, the mephenesin-type compounds have no effect onthe muscle end-plates in ordinary dosage and no not paralyze therespiratory muscles or change the blood pressure. This group ofcompounds has been found to produce reversible paralysis of the skeletalmuscles without significantly affecting the heart or autonomicrespiration and autonomic functions. Since the mephenesin type compoundsantagonize strychnine convulsions, several pharmacological testsdeveloped to date have been based on the degree of antagonism to suchconvulsions. The duration of action of meprobamate or mepromate isreported to be about three times longer than that of mephenesin. Theusefulness of many of these compounds, such as mephenesin, has beenlessened due to their relatively brief duration of action, necessitatingfrequent large doses; and as always workers in the dosages and to cutdown on any untoward side effects.

Standard pharmacological tests in animals have indicated that thecompound -o-methoxyphenoxymethyl-Z-oxazolidone produced by the novelprocess of the present invention has utility as a skeletal musclerelaxant with a high degree of activity against strychnine inanti-convulsant behavior.

The patented prior art describing processes for the compound of thepresent invention can be distinguished. U.S. 2,399,118, 2,437,388,2,437,390 to Homeyer describe generally the preparation of 2-oxazolidonecompounds in which the 5-position is substituted by alkyl or aryl.

However, the preparation of selected 2-oxazolidone ether compounds suchas 5-o-methoxyphenoxymethyl-2- oxazolidone has not been described in theprior art to date.

Therefore, it is an object of the present invention to provide animproved method for preparing 5-o-methoxyphenoxymethyl-Z-oxazolidone.

It is a further object of the invention to provide a novel method ofpreparing 5-o-methoxyphenoxymethyl-Z-oxazolidone from equimolarquantities of urea and 3-o-methoxyphenoxy-Z-hydroxy-l-propyl carbamate.

It is a further object of this invention to provide an improved methodof preparing S-o-methoxyphenoxymethyl-2-oxazolidone as above wherein theurea and the carbamate are rapidly heated to a critical temperature ofabout 180 C. and preferably in the range 185 C.- 200 C.

It is a still further object of the present invention to provide animproved process for preparing 5-o-methoxyphenoxymethyl-Z-oxazolidonewith improved yields up to 55%60% of pure compound.

Other objects of this invention will appear from a consideration of thespecification and claims.

The following examples illustrate the improved process of the presentinvention. Comparative Example A exemplifies the preparation ofS-o-methoxyphenoxymethyl-2-oxazolidone from urea and glyceryl guaiacolether as originally disclosed in my parent application Serial No.680,647, Lunsford, filed August 28, 1957, and modified by the improvedteaching steps of the present proc ess which are applicable to thatrelated urea fusion process as well.

Example 1, exemplary of several runs, teaches the process of the presentapplication and Example 2' illustrates the applicability of the presentprocess to certain other novel S-aryloxy substitutedmethyl-Z-oxazolidones specifically not claimed in the presentapplication.

methyl-Z-oxazolidone A mixture of 39.6 grams (0.2 mol) of glycerylguaiacol ether and 24.0 grams (0.4 mol) of urea was heated in a flaskequipped with a thermometer and ten inch air condenser which was pluggedloosely with a wad of cot ton. The mixture was heated rapidly to thetemperature range of 180 C.-200 C. This was accomplished by placing thereaction flask in a Woods metal bath which had previously been heated to190 0, thus accomplishing a rapid heat transfer. Heating in thistemperature range was continued for five hours and then the reac tionmixture was poured into 200 ml. of water and extracted with chloroform.The chloroform extract was dried over sodium sulfate, filtered andconcentrated. The residue was fractionated at reduced pressure and gavea small amount of low boiling material and 30 grams oxazolidone; boilingpoint 220 C.225 C. at 0.1 mm. The identity of the material wasestablished by mixture melting point determinations with an authenticsample.

Alternatively, the residue from the chloroform extraction wascrystallized from 95% ethanol or acetone. This method of workupconsistently gave yields in the (67.3%) of5-ortho-methoxyphenoxymethyl-Z- order of 40% of white product, meltingin the range of C. 144 C.

Example I.5 ortho methoxyphenoxymethyl 2 0xazolidane A mixture of 24.1grams (0.10 mol) of 3-ortho-methoxyphenoxy-Z-hydroxy-l-propyl carbamateand 6.0 grams (0.10 mol) of urea was heated rapidly to the temperaturerange of 180 C.-200 C., and maintained there for five hours. Thereaction melt was poured into 50% ethyl alcohol, from which the productcrystallized as a white solid. The crude yield was 18.3 grams (82%);melting point 131.5 C.-137 C. Crystallization from water and 95% alcoholgave 9.0 grams (40.3%) of pure 5 ortho methoxyphenoxymethyl 2oxazolidone; melting point 141 C.143 C. This melting point was notdepressed when the material was mixed with an authentic sample. Inadditional runs acetone was used instead of ethyl alcohol withequivalent results.

It was found that when the heating time was reduced to three hours and areaction temperature of l90-200 C. was maintained, equivalent yields (40to 50%) were obtained, but that the yields were appreciably lowered whenthe heating time was further reduced to two hours. It was also foundthat when the temperature was lowered to the range -180 the yield wassignificantly lowered.

When the material was isolated by extraction with chloroform anddistillation, as described under Comparative Example A, the yield ofpure material was 58.5%.

Example II.-5 (3 chloro 6 methylphenoxymethyl)- Z-oxazolidone Aimixtureof 12.70 grams (0.05 mol) of 3-(3-chloro-6-methylphenoxy)-2-hydroxy-1-propyl carbamate and 4.4 grams (0.07 mol)of urea was rapidly heated to 195 C.200 C. and maintained there for fivehours. The reaction mixture was poured into ethyl acetate and washedwith water. The organic layer was dried over sodium sulfate andconcentrated, and the residue which was distilled at 200 C./0.1 mm. ofmercury was collected. Yield: 7.0 grams (58%); the compound appeared asa fine white powder and had a melting point of 104 C.-104.5 C. Whenmixed with an authentic sample the melting point was not depressed.

Analysis.--Calcd. for C H ClNO N, 5.80. Found: N, 5.50.

It is understood that the method of the present invention may bemodified without departing from the spirit and scope thereof. Theinvention is therefore limited only by the scope of the appended claims.

I claim:

1. The method of preparing 5-o-methoxyphenoxymethyl-2-oxazolidone whichcomprises reacting approximately equimolar quantities of urea and 3 omethoxyphenoxy-Z-hydroxy-l-propyl carbamate by heating at a temperatureof at least 180 C. for a period of at least three hours and separatingand recovering said oxazolidone.

2. The method of claim 1 in which the heating is carried out at atemperature range of about C.- 200 C.

3.,The method of preparing S-o-methoxyphenoxy-Z- oxazolidone whichcomprises reacting about 1 mol equivalent of urea with about 1 molequivalent of 3-o-methoxyphenoxy-Z-hydroxy-l-propyl carbamate by rapidlyheating to a temperature range of about 185 C.-200 C. for a period ofabout five hours, extracting crude oxazolidone with a suitable solvent,fractionating said extract and recovering said oxazolidone.

' 4. The method of claim 3 wherein said rapid heating is produced bymeans of an outside heat transfer medium.

5. The method of claim 3 wherein said suitable solvent is selected fromthe group consisting of chloroform and ethyl acetate.

6. The method of preparing S-o-methoxyphenoxymethyl-Z-oxazolidone whichcomprises reacting and heating about 1 mol equivalent of urea with about1 mol equivalent of 3-o-methoxyphenoxy-Z-hydroxy-1-propy\l carbamate byrapidly heating to a temperature range of about 6 185 C.-200 C. for aperiod of about five hours to produce crude oxazolidone andcrystallizing and purifying said crude oxazolidone from an oxygenatedsolvent. 7. The method of claim 6 wherein said oxygenated solvent isselected from the group consisting of acetone, ethyl alcohol and water.

No references cited.

1. THE METHOD OF PREPARING 5-O-METHOXYPHENOXYMETHYL-2-OXAZOLIDONE WHICHCOMPRISES REACTING APPROXIMATELY EQUIMOLR QUANTITIES OF UREA AND 3 - O -METHOXYPHENOXY-2HYDROXY-1-PROXYL CARBAMATE BY HEATING AT A TEMPERATUREOF A LEAST 180*C. FOR A PERIOD OF AT LEAST THREE HOURS AND SEPARATINGAND RECOVERING SAID OXAZOLIDONE.